Simpson Dysmorphia Syndrome

Synonyms of Simpson Dysmorphia Syndrome

Subdivisions of Simpson Dysmorphia Syndrome

Simpson Dysmorphia Syndrome Type 1 (SDYS1)

Simpson Dysmorphia Syndrome Type 2

General Discussion

Simpson dysmorphia syndrome types 1 and 2 are two forms of a rare, X-linked recessive, inherited disorder characterized by unusually large fetuses (prenatal overgrowth) and unusually large babies (postnatal overgrowth). In addition, affected individuals have characteristic facial features, more than two nipples (super-numerary nipples), and multisystemic malformations that may vary from child to child. Chief among these are cardiac malformations, mild to moderate mental retardation, cleft palate, and more than the five fingers and/or toes (polydactyly).

Symptoms associated with the more common form, Simpson dysmorphia syndrome type 1 (SDYS1), are less severe than those presented in SDYS2.

Individuals usually reach an above-average height. The general distinguishing features typically become less apparent in adulthood.

Signs & Symptoms

Simpson dysmorphia syndrome is characterized by an increase in birth weight and length, which may be accompanied by a large protruding jaw, wide nasal bridge, unusually widely-spaced eyes (hypertelorism), upturned or broad nose, large mouth, and short neck.

Other symptoms may include broad, short hands and fingers, underdeveloped (hypoplastic) or absent index fingernails, more than the usual number of digits on the hands and/or feet (unilateral postaxial polydactyly), and webbing between the second and third digits (bilateral syndactyly).

Some individuals affected by Simpson dysmorphia syndrome may have a groove on the midline of the tongue, the lower lip, and the bony ridge in the lower jaw where the teeth are located (inferior alveolar ridge). In addition, affected individuals may have an abnormally enlarged tongue, incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), 13 ribs (as opposed to the usual 12), and/or extra (supernumerary) nipples. Small sacs may protrude from the small intestine (Meckel’s diverticulum), and the testes may not descend into the scrotum (cryptorchidism). Other characteristics found in some affected individuals may include abnormalities of the sacrum and tailbone, such as bony appendages or skin tags, and/or abnormalities of the kidney, such as a kidney containing one or more cysts. In some cases the intestine may fail to rotate during prenatal development (intestinal malrotation), and/or the affected individual may have either an unusually small head (microcephaly) or an unusually large head (megalocephaly).

Individuals with Simpson dysmorphia syndrome type 1 usually have mildly delayed intellectual development that may, in some cases present with mild mental retardation. Further, irregular heartbeats (cardiac arrhythmias) or other heart (cardiac) defects may be components of Simpson dysmorphia syndrome and could be linked with life threatening complications in infancy or with cardiac arrest in adults.

The findings associated with SDYS2 are similar but more severe.

Causes

The mutated gene that is associated with Simpson dysmorphia syndrome type 1 has been traced to gene map locus Xq26. The mutated gene that is associated with Simpson dysmorphia syndrome type 2 has been tracked to gene map locus Xp22.

Clinicians believe that the gene glypican 3 (GPC3) contributes to the control of growth and that changes in this gene may lead to overgrowth. It is thought that organs of the body, such as the heart and liver, reach normal size when GPC3 is available in sufficient concentration. Concentration is sufficient when GPC3, the growth inhibiting factor, balances the growth promoting factors, such as insulin-like growth factor 2, IGF2.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq26″ refers to band 26 on the long arm of the X-chromosome; and “chromosome Xp22″ refers to band 22 on the short arm of the X-chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.

X-linked dominant disorders are also caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Affected Populations

Simpson dysmorphia syndrome is apparent at birth (congenital). The syndrome has been diagnosed only in males, although the carrier females may display symptoms to varying degrees. Between 10 and 20 affected families with SDYS1 have been recorded in the medical literature. The variant SDYS2 has been recorded in 1 family.

Related Disorders

Symptoms of the following disorders can be similar to those of Simpson dysmorphia syndrome. Comparisons may be useful for a differential diagnosis:

Beckwith-Wiedemann syndrome (BWS) is a rare genetic disorder. It is characterized by a broad range of symptoms and findings that vary in location and severity from case to case. However, in many individuals with the syndrome, associated features may include above average weight and length at birth and/or increased growth after birth (postnatally); an unusually large tongue (macroglossia); enlargement of certain abdominal organs (visceromegaly); and/or abdominal wall defects. BWS may also be characterized by low blood sugar levels within the first days of life (neonatal hypoglycemia); advanced bone age, particularly up to age four, and/or an increased risk of developing certain childhood cancers.

Cleft lip and/or palate are common malformations that are noticeable at birth. A cleft is an incomplete closure of the lip or palate, or both. This defect is caused when the pair of long bones that form the upper jaw (maxillae) do not fuse properly during the development of the embryo. The cleft may be barely noticeable or result in severe deformities requiring surgical correction. When cleft lip and/or palate occur as part of another syndrome, the cause is that of the syndrome. (For more information on this disorder, choose “Cleft Lip and Cleft Palate” as your search term in the Rare Disease Database.)

Craniometaphyseal dysplasia is a rare genetic disorder characterized by distinctive facial features that include a wide nasal bridge, widely spaced eyes (hypertelorism), overgrowth of the bone over the eyes, a small jawbone, and incomplete development of the sinuses. Multiple deformities of the teeth and bones may also be present. Intelligence is usually normal. (For more information on this disorder, choose “Craniometaphyseal Dysplasia” as your search term in the Rare Disease Database.)

Oro-facial-digital syndrome is a rare genetic disorder in which there have been four types identified. Symptoms common to all types include episodes of neuromuscular disturbances, split (cleft) tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue (frenulum), a broad based nose, vertical folds of the skin covering the inner angle of the eyelids (epicanthic folds), more than the normal number of fingers and/or toes, shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “Oro-Facial-Digital” as your search term in the Rare Disease Database.)

Oto-palato-digital syndrome (OPD) types I and II are rare genetic disorders which are predominantly found in males. Females may be mildly affected with some of the symptoms. Some of the characteristics of both types I and II may be cleft palate, a downward slant of the opening between the upper and lower eyelids, hearing loss, and/or short fingers and toes. Symptoms of OPD I can include dislocation of the head of one of the bones of the forearm (radius), mild dwarfism, and/or underdeveloped bones of the face. Symptoms of OPD II can include a small head, fingers that are bent and overlap, or curved long bones of the forearm and legs. (For more information on this disorder, choose “Oto-Palato-Digital” as your search term in the Rare Disease Database.)

Larsen syndrome is a multi-system genetic disorder that is present at birth. It is characterized by multiple bone dislocations and abnormalities, an extremely high arch of the foot, non-tapering cylindrically shaped fingers, and an unusual facial appearance. (For more information on this disorder, choose “Larsen” as your search term in the Rare Disease Database.)

Standard Therapies

Treatment of Simpson Dysmorphia Syndrome is symptomatic and supportive. Genetic counseling may be of benefit for patients and their families.

Individuals with cleft palate require the coordinated efforts of a team of specialists. Pediatricians, dental specialists, surgeons, speech pathologists, and psychologists must systematically and comprehensively plan treatment and rehabilitation. The palate may be repaired surgically or covered by an artificial device that closes or blocks the opening. Speech and language development need to be assisted by a speech pathologist during the preschool years.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

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